Powder Technology 294 (2016) 113–118

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Powder Technology

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The effect of water activity on granule characteristics and tablet

properties produced by moisture activated dry granulation (MADG)
Hiroshi Takasaki a, Etsuo Yonemochi b,⁎, Masanori Ito a, Koichi Wada a, Katsuhide Terada c
a
Nippon Boehringer Ingelheim Co., Ltd., 6-7-5 Minatojima, Chuou-ku, Kobe, Hyogo 650-0047, Japan
b
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, 142-8501 Tokyo, Japan
c
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan

a r t i c l e i n f o a b s t r a c t

Article history: This study evaluated the effects of changing the amount of added water for moisture activated dry granulation
Received 26 December 2014 (MADG) on the resulting granule characteristics and tablet properties. Water soluble fillers and binders were
Received in revised form 18 July 2015 pre-mixed in a granulator, and the binder was activated by a small amount of water to form granules. The amount
Accepted 7 February 2016
of added water was defined as the percentage of granulation water by mass to charged powder. Granules made
Available online 11 February 2016
with 0.0%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, and 5.0% (w/w) added water were evaluated in this study. Furthermore, the
Keywords:
effect of free water content on tablet characteristics was investigated by measuring water activity.
Moisture activated dry granulation The Hausner ratio (HR) of MADG granules is significantly decreased by increasing the amount of added water up
Water activity to 1.0% (water activity over 0.39). However, the HR of MADG granules did not change with further increase in
Free water water activity (added water over 2.5%). The free water content (water activity over 0.61, water added over
Tablet disintegration 2.5%) may reach a limit in improving the flowability of MADG granules.
MADG tablet tensile strength was increased along with the increased water activity when the added water
amount was from 0.0% to 2.5%. However, MADG tablet tensile strength prepared with 3.0% or 5.0% added
water was lower than in other tablets. Similarly, MADG tablet tensile strength was increased with increasing
water activity from 0.0% to 2.5% added water. Yet, the magnitude of the negative slope between 2.5% and 5.0%
added water was approximately ten times greater compared to the magnitude of the slope between 0.0% and
2.5% added water. By increasing the amount of added water over 2.5%, the excess amount of free water may
have caused the decreasing tensile strength of the MADG tablets.
MADG tablet initial wetting was correlated with water activity, and free water content was shown to have signif-
icant impact on the initial wetting of MADG tablets. Furthermore, this association between free water content
and initial wetting of MADG tablets had a significant impact on tablet disintegration. Free water content had a
low or minor impact on tablet porosity and capillary wetting.
© 2016 Elsevier B.V. All rights reserved.

1. Introduction granulation, and a final blending with further functional excipients,

High-shear granulation (HSG) is widely used in the pharmaceutical
industry to improve powder flow for the prevention of segregation.
From a processing perspective, HSG is inferior to direct compression
or dry granulation due to the need for a further drying stage after ag-
glomeration, requiring additional equipment such as a tray dryer or a
fluidized-bed dryer.
Therefore, moisture-activated dry granulation (MADG) may be an
interesting and alternative way to combine the benefits of high-shear
granulation with the avoidance of an additional drying stage as de-
scribed above. MADG was initially described by Ullah et al. in 1987 [1].
The entire process can be completed within a conventional high-shear
granulator, with initial pre-blending of all components intended for
⁎ Corresponding author.
such as disintegrants or lubricants just prior to compression. Therefore,
a transfer of granule intermediates to other equipment in between pro-
cess steps is avoided, saving processing time. Additionally, because
transfer steps are the main source of exposure, MADG is the ideal gran-
ulation process for the manufacturing of solid dosage forms of highly
potent compounds.
MADG can be divided into two stages: the agglomeration stage and
the moisture absorption stage [2,3]. Initially, the active pharmaceutical
ingredient (API), water soluble fillers, and binders are pre-mixed in
the granulator, and the binder is then activated by a small amount of
water to form granules. MADG typically needs significantly less (1–4%
(m/m)) granulation liquid compared to the conventional HSG process
[2]. During the absorption stage, the moisture within the granules is re-
duced and distributed uniformly throughout the blend by subsequent
addition of a water-insoluble filler-component, such as an absorbent
powder.

http://dx.doi.org/10.1016/j.powtec.2016.02.013
0032-5910/© 2016 Elsevier B.V. All rights reserved.
114 H. Takasaki et al. / Powder Technology 294 (2016) 113–118

Water content is one of the most important parameters for wet
granulation; many researchers have investigated the importance of
the amount of added water in HSG. Sherif et al. described the effect of
different HSG parameters on granule characteristics, including granule
size and compressibility. According to their results, the amount of
added water had the greatest impact on granule size, density, and gran-
ule compressibility [4,5]. Preeetanshu et al. also described the effect of
different HSG process parameters on granule characteristics using an
experimental and modeling approach. They concluded that the amount
of added water had the greatest impact on granule characteristics [6].
Limin et al. reported that the increased size of granules was an impor-
tant factor of over-granulation in HSG [7].
In MADG, the binder is activated by a small amount of water, defined
as the percentage of granulation water to charged powder by mass. Dur-
ing the granulation step a wet mass is produced which must be plastic
and deform when water is added. The composition of the wet mass is
critical in determining the properties of the particle produced. This pro-
cess is also sensitive to variations in raw materials. For the absorption
stage, the moisture absorbents were added, and they absorbed excess
water from the wet mass. During this process the existing water were
redistributed throughout the granules. Roja et al. reported that the me-
chanical and disintegrating properties of several pharmaceutical mate-
rials are related to their moisture content and water uptake capacity
[8]. Because the amount of added water for MADG is significantly
lower (1–4%) than that for HSG (normally over 20%) to create agglom-
eration and to skip the drying process, the amount of added water
for MADG may have an impact on granule characteristics and tablet
qualities. The amount of added water is one of the most important
parameters for MADG. However, to the best of our knowledge, most
studies to date have only made comparisons between MADG and
other manufacturing process (HSG, direct compression, dry granula-
tion) [1,9–11]. Christensen et al. described the impact of the amount
of added water on granule and tablet characteristics prepared by
MADG [12]; however, in their study, the amount of added water was
only 1.5% and 2.5%, and the impact of added water amount was not clar-
ified for MADG.
The aim of this study was to evaluate the amount of added water for
MADG and the resulting granule characteristics and tablet properties.
Amounts of added water (w/w) were 0.0%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,
and 5.0%. Furthermore, the effects of free water content on tablet prop-
erties were investigated by measuring water activity, as well as mea-
surement of the contact angle of the water on the tablet surface.
2. Materials and methods
2.1. MADG
Table 1 shows the formulations used in this study. Batches of 250 g
were processed in a high-shear granulator (Diosna P1/6, Diosna)
equipped with a 1 L granulation bowl. Processing parameters were
kept constant throughout the agglomeration (1 min) and massing
(3 min) stages: impeller 500 rpm, chopper 1200 rpm. Fine grade lactose
monohydrate (Granulac 200, Meggle) containing small quantities of
iron oxide red (Univar Ltd.) was initially mixed with the binder
Polyvidone (Povidone K12, BASF), and granulated by spraying water
for 15 s (nozzle diameter 0.3 mm, atomizing air pressure 2.5 bar) into
the granulation bowl. The amounts of added water (w/w) were 0.0%,
1.0%, 1.5%, 2.0%, 2.5%, 3.0%, and 5.0%. In a pretrial, the high-viscosity
grade of Polyvidone (Povidone K25) did not agglomerate sufficiently
by addition of these small amounts of water. Therefore, a low-
viscosity grade was chosen, as described in previous reports [2,3]. For
the 2 min absorption stage, the moisture absorbents microcrystalline
cellulose (Avicel PH102, FMC) and colloidal silicon dioxide (Aerosil
200, Degussa) were added when the chopper was stopped. Low-
moisture grade microcrystalline cellulose (Avicel PH 200 LM, FMC) is
highly suitable as an absorbent for MADG due to its very low water con-
tent [2]. However, normal grade Avicel PH102 was chosen for use in this
study, because a previous study reported that the low-moisture grade
Avicel PH200LM did not demonstrate any advantages compared to
Avicel PH102 [13].
Finally, the disintegrant crospovidone (Kollidon CL, BASF), and pre-
sieved lubricant magnesium stearate (Magnesium stearate vegetable,
Faci) were blended directly into the granulator for 1.5 min and
0.5 min, respectively, with a reduced impeller speed of 250 rpm. The
final blends were sieved by a conical sieving machine (1.0 mm rasp
sieve, Quadro Comil U5, Powrex).
2.2. Particle size distribution
The particle size distributions of the final blends were measured by
sieve analysis (Robot Shifter RPS-95, Seishin) employing the following
screens: 355 μm, 250 μm, 180 μm, 125 μm, 90 μm, 75 μm, and 63 μm,
for a sifting time of 5 min on vibration level 4 and pulse interval of 1 s
(n = 1). Interpolation nodes for d50 were iterated using the software
Easysieve (Retsch).
2.3. Bulk and tapped density
Bulk and tapped densities of the final blends were determined in a
100 mL sample cup on a powder property measurement system (Pow-
der Tester PT-R, Hosokawa micron) by applying 180 taps (n = 1). The
Hausner ratio (HR) as a surrogate for flowability was calculated as the
ratio of tapped and bulk density: (ρ tapped/ρ bulk). The flowability
was classified according to US Pharmacopedial Convention benchmarks
from excellent (1.00–1.11), good (1.12–1.18), fair (1.19–1.25), to pass-
able (1.26–1.34).
2.4. Loss on drying

Table 1
Loss on drying (LOD) of the final blends was measured by moisture
Formulation and batch size of MADG tablets in process stage.
content balance (HG63-P, Mettler Toledo) at 105 °C for 10 min (n = 1).
Process stage Amount of added 0%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 5.0%
water⁎
% mg/tab g/batch Table 2
1 Granulac 200 64.5 129.0 161.25 Granule characteristics and tablet mass variability.
Iron oxide red 0.1 0.2 0.25
Amount of added water (%) 0.0 1.0 1.5 2.0 2.5 3.0 5.0
Povidone K12 5.0 10.0 12.50
2 Avicel PH 102⁎⁎ 26.4 52.8 66.0 D50(μm) 58 80 91 100 99 103 123
Aerosil⁎⁎ 0.5 1.0 1.25 Bulk density (g/mL) 0.55 0.54 0.54 0.54 0.54 0.54 0.52
3 Crosspovidone 2.5 5.0 6.25 Hausner ratio 1.47 1.47 1.28 1.23 1.21 1.18 1.20
Magnesium stearate 1.0 2.0 2.50 Loss on drying (%) 1.77 2.58 3.01 3.35 3.63 4.16 5.49
#
Total 100.0 200.0 250.0 Mass variation (%) 1.26 0.45 0.50 0.43 0.95 0.80
Water activity (−) 0.24 0.39 0.49 0.56 0.61 0.66 0.78
1 = Agglomeration/massing; 2 = Moisture absorption; 3 = Main and final blending.
Ture density (g/cm3) 1.51 1.51 – 1.51 – 1.51 –
⁎ The percentage of the water was calculated on 250 g.
⁎⁎ Moisture absorbents. #
Bad granule flow.
 H. Takasaki et al. / Powder Technology 294 (2016) 113–118
2.5. Preparation of tablets
The final blends were compressed to flat-faced tablets with a diam-
eter of 8 mm and mass of 200 mg on an eccentric press (FlexiTab,
Manesty) at different compression forces of 2.5 kN, 5.0 kN, 7.5 kN,
10.0 kN, and 15.0 kN.
2.6. Water activity
The water activity of the final blends was measured using a water
activity meter (LabMaster-aw basic, Novasina) (n = 1).
2.7. Tablet hardness and thickness
Hardness of the tablets and tablet thickness were measured using a
tablet hardness tester (TBH425, ERWEKA) (n = 10). Tensile strength
was calculated as 2 F/(π ∗ D ∗ T): where F is the hardness, and D and T
are the diameter and thickness of the tablets, respectively.
2.8. Tablet disintegration time
Disintegration time of the tablets was measured at 37 °C using a dis-
integration tester (NT-400, Toyama) at 30 cycles/min (n = 6). No discs
were added. The test medium was water.
2.9. Tablet porosity
Tablet porosity (ε) was calculated by employing the equation ε =
1 − (m/ρ true ∗ V), where m and V are mass and volume of the tablets,
respectively. True density (ρ true) was measured using a mercury pen-
etration porosimeter (Amico) (n = 1).
2.10. Contact angle
Contact angle of the tablets was measured using a contact angle
meter (FTA 1000, First Ten Angstroms). The needle was set to drop
2.0 μL of water onto the tablet surface. Contact angle was recorded
from 0 to 1.3 s. Data collection speed was 60 fps (n = 3).
The relationship between time and contact angle was calculated
using the modified Washburn equation, where the time was inversely
proportional to the contact angle
1 γ :ρ2  c
¼ L 2 t
cos θ η:w
γL surface free energy of the liquid (N/m).
ρ density of the liquid (kg/m3).
θ contact angle (degree).
η viscosity of the liquid (Pa·s).
c constant.
W weight of absorption liquid.
3. Results and discussion
3.1. MADG and granule characteristics
Table 2 shows Granule characteristics and tablet mass variability.
Granulation using 0.0% (physical mixture), 1.0%, 1.5%, 2.0% and 2.5%
water was performed without problem. Increasing the amount of
added water to over 3.0% resulted in wall adhesion and formation of
big lumps. The mean particle size of MADG granules made with 0.0%
water (physical mixture) was 58 μm; the HR of these granules was
1.47, indicating very poor granule flow. Therefore, MADG granules
made with 0.0% water were unable to produce a tablet due to poor
115
granule flow and sticking during the tableting process. On the other
hand, MADG granules made with 1.0% water were able to produce tab-
lets without granule flow problems or sticking; the mass variability of
these tablets were 1.26%. The amount of added water for the standard
high shear granulation (HSG) process in our previous study was 20%
[13], using a composition almost the same as the MADG formulation
in the present study. Consistent with previously reported results, HSG
requires more granulation water than MADG [1,8]. A mere 1.0% of
water had a significant impact on the MADG granule properties, sug-
gesting that the amount of added water may be a more significant factor
affecting granule properties than it is for HSG. Furthermore, the water
content of MADG granules may have a significant impact on granule
characteristics.
Water content can be divided into two types: free water and bound
water content. Measurement of total water content may not be a good
approach for understanding the effects of water on granule properties
[14].Water activity is not the measure of water amount, but the measure
of free water amount [15]. High free water content encourages bio-
chemical reaction, resulting in a shorter shelf life of the sample [16]. In
the present study, the free water content in the MADG granules was
evaluated by measuring water activity.
Fig. 1 shows the HR of MADG granules as a function of water activity.
The HR of MADG granules made with 1.0% water (1.47, d50: 80 μm) was
the same as the HR of MADG granules made with 0.0% water (1.47, d50:
58 μm). The variability in mass of MADG tablets made with 1.0% water
was significantly lower (1.26%) than those made with 0.0% water, sug-
gesting that the particle size of MADG granules may have an impact
on tablet mass variability. (See Fig. 2.)
By increasing the amount of added water over 1.0% (water activity
over 0.39), the HR of MADG granules was significantly decreased. It is
known that dry powder exhibiting cohesiveness due to electrostatic
charging may become more free-flowing as atmospheric humidity in-
creases [17]. Therefore, the lower threshold for free water content
(water activity) was determined to be 0.39, with free water content
having a positive impact on MADG granules flowability when the
amount of added water is over 1.0%.
On the other hand, the HR of MADG granules did not change (about
1.20) with further increase in water activity (amount of added water
over 2.5%). Therefore, free water content (water activity over 0.61)
reached an upper limit for improving MADG granule flowability.
3.2. Factors affecting tensile strength of MADG tablets
ð1Þ
The effect of an increased amount of added water on tensile strength
was investigated. Fig. 1 shows MADG tablet tensile strength as a func-
tion of compression force. The MADG granules made with 0.0% water
(physical mixture) were unable to produce tablets due to poor granule
flow and sticking during the tableting process. Therefore, MADG tablets
made with 0.0% water were produced by the FlexiTab vibration mode
Fig. 1. Water activity vs. Hausner ratio ■; Amount of added water: 0.0% and 1.0% □;
Amount of added water: 1.5%, 2.0%, 2.5%, 3.0% and 5.0%.
116 H. Takasaki et al. / Powder Technology 294 (2016) 113–118
Fig. 2. Compression force vs. tensile strength of MADG tablets (Mean n = 10, SD).
for improving granule flow. The punch and dies were coated with mag-
nesium stearate by a rolling pin to alleviate the sticking tendency.
MADG tablets, tensile strength, produced using a compression
force of 10 KN, increases by the amount of water: 0% (2.95 MPa), 1.0%
(3.24 MPa), 1.5% (3.36 MPa), 2.0% (3.46 MPa), and 2.5% (3.48 MPa). How-
ever, MADG tablet tensile strength made with 3.0% water (2.57 MP) or
5.0% water (0.65 MPa) was lower compared to other tablets.
Many studies have investigated the effect of moisture content on
tablet compactibility; one such study found that with paracetamol pow-
der, the mean yield pressure decreased with increasing moisture con-
tent [18]. However, another showed tensile strength reached a peak
and started to decrease when moisture content was approximately dou-
bled [19]. These results suggest increasing or decreasing the amount of
moisture can increase or decrease the tensile strength, with the exact
change dependent on the moisture content of the powders [20].
Fig. 3 shows MADG tablet tensile strength as a function of water ac-
tivity. MADG tablet tensile strength was positively correlated with
water activity from 0.0% (water activity 0.24) to 2.5% added water
(water activity 0.61) (y = 1.45x + 2.63, R2 = 0.97), consistent with a
previous report [18]. It is known that water activity is associated with
free water content; therefore, it is likely that free water content has a
positive impact on MADG tablet tensile strength between 0.0% and
2.5% added water.
By increasing the amount of added water over 2.5% (water activity
0.61), the tensile strength of tablets prepared by MADG granules de-
creased significantly between 2.5% water (water activity 0.61) and
5.0% added water (water activity 0.78). MADG tablet tensile strength
was negatively correlated with water activity between 2.5% and 5.0%
added water (y = − 16.07x + 13.25, R2 = 1.0). As shown in Fig. 3,
the magnitude of the negative slope between 2.5% and 5.0% added
water was approximately ten times larger than that of the slope
between 0.0% water and 2.5% added water. Based on the granule
Fig. 3. Water activity vs. tensile strength of MADG tablets (Compression force: 10 kN) ◆;
Amount of added water: 0.0% ,1.0%,1.5%, 2.0% ◇; Amount of added water: 2.5%, 3.0% and
5.0%.
Fig. 4. Disintegration time vs. tensile strength of tablets (Mean n = 6, min/max).
characteristics results, the HR of MADG granules did not change
(about 1.20) when the amount of added water was over 2.5%.
If humidity is further increased, liquid bridge formation results in a
return to cohesive behavior [17]. Sticking tendencies were observed
during the MADG tableting process using 5.0% added water. Therefore,
the cohesive behavior of MADG granules significantly increased by in-
creasing water activity over 0.61 (amount of added water 2.5%), sug-
gesting an upper threshold of free water (water activity) content was
0.61. We defined that this peak in MADG tablet tensile strength indicat-
ed the maximum amount of free water. When an additional 2.5% of
water was added over this threshold (water activity 0.61), the excess
amount of free water may have been the underlying reason of decreas-
ing MADG tablet tensile strength.
3.3. Effect of added water amount on MADG tablet disintegration time
The effect of the amount of added water on disintegration time was
investigated. Fig. 4 shows the disintegration time of MADG tablets as a
function of tensile strength. MADG tablets made with 0.0%, 1.0%, 2.0%,
and 3.0% added water were used for this evaluation.
Disintegration time of MADG tablets made with 0.0% water (80 s:
tensile strength 2.98 MPa) and 1.0% (75 s: tensile strength 3.24 MPa)
demonstrated fast disintegration compared to other tablets. Further in-
creasing the amount of added water increased the disintegration time
as shown in MADG tablets made with 2.0% water (105 s: tensile
strength 3.0 MPa) and 3.0% water (148 s: tensile strength 2.75 MPa).
These results suggested that the amount of added water may have a sig-
nificant impact on the disintegration time of MADG tablets.
3.4. Wettability measurement (contact angle profile)
Tablet wettability and porosity were investigated due to these vari-
ables' association with tablet disintegration [21].
Fig. 5. Time profile of contact angle (Mean n = 3) Initial wetting: contact angle at 0 s
Capillary wetting: contact angle at 0.3 s.
 H. Takasaki et al. / Powder Technology 294 (2016) 113–118
Fig. 6. Porosity vs. water activity (Mean n = 10, SD).
Fig. 5 shows the contact angle profiles of the MADG tablets. Tensile
strength of tablets prepared by MADG granules was about 3.0 MPa for
this evaluation. The amount of added water had a significant impact
on the contact angle of MADG tablets. Takasaki et al. reported that the
wetting behavior was divided into two phenomena: initial wetting
and capillary wetting. Initial wetting was defined as wetting of the sur-
face of the tablet bed, after which the water penetrates into the tablet,
defined as capillary wetting [13]. The initial wetting was measured at
a contact angle of 0.0 s when water made an initial contact with tablet
surface, while capillary wetting was measured at a contact angle of
0.3 s during water was penetrating into the tablet.
Most studies assert that disintegration time is able to be evaluated
by wettability of the tablet [22–24]. However, there has been little
study on the association between free water content and tablet wetta-
bility. In the present study, this was evaluated in MADG tablets by mea-
suring water activity.
3.5. Effect of water activity on wettability
Figs. 6 and 7 show MADG tablet porosity, initial wetting and capillary
wetting, respectively, as a function of water activity. MADG tablet ten-
sile strength was about 3.0 MPa for this evaluation. A linear approxima-
tion was used for data evaluation.
There were no significant differences in porosity of the MADG tab-
lets. MADG tablet porosity showed only a weak correlation with water
activity (y = −0.048x + 0.162, R2 = 0.45). Because water activity is as-
sociated with free water content, these results suggest that free water
content had a weak impact on tablet porosity.
MADG tablet initial wetting correlated with water activity (y =
11.63x − 1.93, R2 = 0.91), as did MADG tablet capillary wetting (y =
1.32x + 0.63, R2 = 0.79). The correlation coefficient of the initial wet-
ting (R2 = 0.91) was much higher than the correlation coefficient of
the capillary wetting (R2 = 0.79), and the slope of the initial wetting
Fig. 7. Initial and capillary wetting vs. water activity (Mean n = 3, SD).
117
(11.63) was approximately 9 times larger than the slope of the capillary
wetting (1.32). Wettability and porosity is associated with disintegra-
tion time. These results suggested that water activity, and therefore
water content, may have a significant impact on MADG tablet initial
wetting. On the other hand, free water content had low or minor impact
on MADG tablet porosity and capillary wetting.
4. Conclusions
We produced MADG tablets made with 0.0%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, and 5.0% added water. By increasing the amount of added water
over 1.0% (water activity over 0.39), the HR of MADG granules was sig-
nificantly decreased. The lower threshold of free water content (water
activity) level was 0.39; free water content may have a positive impact
on the flowability of MADG granules when the amount of added water
is over 1.0%. However, further increase in water activity over 2.5% added
water did not change the HR of MADG granules. Therefore, free water
content (water activity over 0.61, amount of added water over 2.5%)
reached an upper limit in improving the flowability of MADG granules.
The tensile strength of MADG tablets gradually increased with in-
creasing amount of added water, from 0.0% to 2.5%. However, the
MADG tablet tensile strength made with 3.0% or 5.0% added water
was lower than in other tablets. MADG tablet tensile strength correlated
with water activity between 0.0% and 2.5% added water, suggesting free
water content may have a positive impact on MADG tablet tensile
strength between 0.0% and 2.5% added water. Upon examination, the
magnitude of the negative slope between 2.5% and 5.0% added water
was found to be about ten times greater compared to the magnitude
of the slope between 0.0% and 2.5% added water, demonstrating that
the upper threshold of free water content (water activity) was 0.61
(2.5% added water). Further addition of water past this threshold led
to an excess amount of free water content, which may have caused
the decrease in MADG tablet tensile strength.
Tablet wettability and porosity were also investigated due to these
variables' association with tablet disintegration time. MADG tablet po-
rosity showed only a weak correlation with water activity; however,
both MADG tablet initial wetting and capillary wetting positively corre-
lated with water activity. Interestingly, the correlation coefficient of ini-
tial wetting was much higher than that of capillary wetting. Because the
initial wetting of MADG tablets correlated with water activity, the free
water content may have a significant impact on the initial wetting of
MADG tablets. This relationship between free water content and initial
wetting of MADG tablets had a significant impact on tablet disintegra-
tion. On the other hand, free water content had low or minor impact
on the porosity and capillary wetting of MADG tablets.
Acknowledgements
We thank Ms. Ono from Nippon Boehringer Ingelheim Co., Ltd. for
her assistance with the water activity measurement.
This project was supported in part by a Grant-in-Aid for Scientific
Research (C), Japan Society for the Promotion of Science (KAKENHI
Grant Number 26460048).
We thank Jasco International Co., Ltd. for their support with the con-
tact angle measurement.
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